1. Field of the Invention
The present invention relates to compositions for the prevention and treatment of cataract formation in the crystalline lens of the eye
2. Discussion of the Background
Aging-related cataract is a gradual opacification of the crystalline lens of the eye, which is presently treated by surgical removal and replacement of the cataractous lens. Cataracts are believed to be a disease of multifactorial origin involving many of the same processes that characterize the process of aging in other tissues. Data accumulated over a period of years from the work of many laboratories indicates that once begun, cataract development probably proceeds via one or more common pathways or processes that culminate in damage to lens fibers. Since cataract is already a slowly progressing disease which occurs predominantly in the elderly, a significant retardation of its rate of development could eliminate the need for many surgical cataract extractions. This reduction would provide tremendous benefits both to individual patients and to the public health system.
Based on research from the inventors and others, several processes have been proposed as crucial factors in cataractogenesis. These processes include oxidation, phase separation phenomena and proteolysis. With the hypothesis that one or more of these processes probably represent "common pathways" involved in lens opacification, the inventors initiated an effort to screen compounds which might inhibit these particular processes for their potential as anti-cataract agents. In keeping with the likelihood that the disease is multifactorial, the inventors tested the agents not only individually but in various combinations as well.
One active area of medical research has been an investigation of the role that free radical scavengers and antioxidants may play in the prevention and treatment of diseases caused by oxidative stress. The focus of many such investigations has been upon biochemical pathways that generate reducing power in cells, for example, glutathione synthesis and cycling. Enzymes that reduce activated oxygen species, such as superoxide dismutase, have also been studied to determine whether they diminish cellular oxidative stress. Compounds for inhibiting lipid oxidation in cell membranes by direct radical scavenging have also been considered to be promising therapeutic interventions. The administration of compounds such as vitamin E, carotenoids, selenium compounds and vitamin C (ascorbate), for their antioxidant effects, is known in the popular culture.
There are many reviews in the literature of in vitro and clinical studies of the medical effect of antioxidants and free radical scavengers (references 1-3, below). Thiol compounds have been of particular scientific interest, because glutathione cycling plays a role in maintaining the redox balance in cells. Selenide compounds having glutathione peroxidase activity, for example, are the subject of U.S. Pat. No. 5,321,138. Thiol derivatives of amino acids have also been studied as antioxidants. In particular, mercaptopropionyl glycine (MPG) has been investigated for it effect in reducing cataract formation (4).
In the present invention, the nitroxide family of radicals is of particular interest. Nitroxides are free radicals that are stable, and which are reducible to their corresponding hydroxylamines. Nitroxides were originally of interest to physical chemists due to their paramagnetic properties, allowing their use as "spin-labels" in electron paramagnetic resonance studies. These compounds have more recently been studied because of their radical scavenging properties; nitroxides mimic the enzymatic activity of superoxide dismutase (5-8). Nilsson et al. disclosed, in WO 88/05044, that nitroxides and their corresponding hydroxylamines are useful in prophylaxis and treatment of ischemic cell damage.
Reddan et al. (9) have investigated the use of the nitroxide TEMPOL to protect lens epithelial cells from hydrogen peroxide damage in vitro. Mitchell et al., in U.S. Pat. No. 5,462,946, also disclose use of nitroxides (such as TEMPOL) to protect lens epithelial cells from oxidative damage. However Mitchell and his colleagues have also reported that only the nitroxide TEMPOL protects cells from oxidative damage, and that the corresponding hydroxylamine TEMPOL-H (the reduced nitroxide) affords no such protection (12, 13).
In spite of years of sustained study into the cause and treatment of cataracts, a clinically useful non-surgical treatment that retards the development of age-related cataracts has eluded researchers. Sorbitol-lowering drugs (aldose reductase inhibitors) have been found to have some effect in retarding the development of cataracts in rats with high galactose intake. Aspirin, acetaminophen and ibuprofen have also been shown to delay experimental cataracts. Bendazac has been found to protect lens proteins in vitro, and to delay the onset of cataracts in x-ray irradiated rats. Yet other treatments that have been proposed for the treatment of cataracts include vitamins, aminoguanidine, and various herbal preparations. None of these treatments has yet been demonstrated to be clinically useful.
It is therefore an object of this invention to provide a clinically useful, non-surgical treatment to retard or prevent the development of cataracts in the crystalline lens of the eye.
This and other objects of the invention will be understood more clearly by reference to the following detailed description and drawings.